The aim of this proposal is to understand the molecular basis of aging by SIR2 genes in mammals. This gene determines the life span in yeast and C. elegans. The activity of SIR2, NAD-dependent protein deacetylase, allows cells to couple metabolism to aging. SIR2 appears to slow aging and extend life span in times of stress or scarcity. In particular, SIR2 mediates longevity in yeast in response to calorie restriction (CR). In mammals, there are seven SIR2 homologs. This proposal focuses on the ortholog, SIRT1, which possesses the same enzymatic activity as SIR2. Previous work showed that SIRT1 can promote survival of cultured mammalian cells in response to oxidative stress by deacetylating and down-regulating p53. In this proposal, we undertake a systematic study of the functions of SIRT1 in mammals. This project includes an identification and study of mammalian proteins that interact with SIRTI. Also, the project examines the relationship between SIRT1 and two primary features of CR in mammals; reduction in white fat and sterility. Finally, the project will study genetically altered mice in which SIRT1 is absent or over expressed. This project will enable us to understand the regulation of aging in mammals by SIRTI. It may also have implications for diseases of aging, such as cancer, cardiovascular disease, diabetes, and neurodegenerative disease.